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Unraveling the Role of Microglial Innate Immune Activation in Primary Mitochondrial Disease

Award Number: F30HD123816
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/14/2026
PERIOD OF PERFORMANCE END DATE: 09/13/2030

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Unraveling the Role of Microglial Innate Immune Activation in Primary Mitochondrial Disease - PROJECT SUMMARY Mitochondrial diseases are among the most prevalent inborn errors of metabolism, affecting a minimum 1 in 5,000 live births. They can be fatal in children as a limited mechanistic understanding has hindered the development of efficacious therapeutics. POLG, the nuclear gene that encodes the catalytic subunit of mitochondrial DNA polymerase γ, is the most commonly pathogenically affected gene in inherited mitochondrial disease. Pediatric POLG disease typically manifests as intractable epileptic encephalopathy followed by progressive neurologic decline and is frequently unmasked or exacerbated by infectious stress. This clinical course implicates immune activation in POLG disease pathogenesis, yet the contribution of microglia, the resident immune cell of the CNS, remains poorly defined. Based on mounting evidence that i) POLG dysfunction enhances innate immune activation ii) microglia can propagate neuroinflammatory cascades that promote epilepsy and neuronal loss iii) POLG microglia are pathogenically dysfunctional as evidenced by our preliminary data, this proposal is built around the central hypothesis that POLG deficiency intrinsically promotes maladaptive microglia activation, leading to aberrant neuroinflammation that promotes neurodegeneration and epileptogenesis. This proposal seeks to address the gap in knowledge of how POLG deficiency alters human microglial function, innate immune signaling, and contributions to CNS function. Therefore, the project goal is to test the hypothesis that POLG deficiency enhances human microglial innate immune signaling in vitro (Aim 1) and in a xenotransplantation model (Aim 2), resulting in deleterious microglial responses to immune stimuli and neuronal dysfunction. By leveraging genomic, electrophysiologic, and pharmacologic techniques, these studies will evaluate microglial activation as a potential mechanistic driver of POLG disease CNS pathology. The long- term goal is to identify targetable immune pathways mediating POLG disease progression. The proposed research will be conducted in the Coufal laboratory at UC San Diego, which specializes in human induced pluripotent stem cell models of neuroimmunology. Through integrated graduate coursework, mentorship, and hands-on learning, Kaitlyn will gain experience in stem cell modeling systems for human brain cell types and develop skills to probe hypotheses related to neuroimmunology and mitochondrial biology. These skills will be invaluable for the completion of the proposed research and for Kaitlyn’s future career as a physician-scientist.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $43,770 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	1	9/10/2026	NEW	$43,770
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	001	1	9/10/2026	NEW	$0
														Subtotal = $43,770

Grand Total All Awards = $43,770

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Unraveling the Role of Microglial Innate Immune Activation in Primary Mitochondrial Disease

Award Number: F30HD123816

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/14/2026

PERIOD OF PERFORMANCE END DATE: 09/13/2030

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